Ezurpimtrostat Receives FDA Orphan Drug Designation for Liver Cancer Subtype


The FDA gives orphan drug designation to ezurpimtrostat, an investigational autophagy inhibitor that may benefit patients with hepatocellular carcinoma.

Investigational agent ezurpimtrostat (GNS561) has received orphan drug designation from the FDA for the treatment of patients with hepatocellular carcinoma (HCC), according to a press release from Genoscience.1

Investigators are also assessing ezurpimtrostat in combination with atezolizumab and bevacizumab for patients with hepatocellular carcinoma in the phase 2b ABE-Liver trial.

Investigators are also assessing ezurpimtrostat in combination with atezolizumab and bevacizumab for patients with hepatocellular carcinoma in the phase 2b ABE-Liver trial.

The orphan drug designation followed data from a phase 1/2a trial (NCT03316222) designed to assess the feasibility and safety of administering ezurpimtrostat to patients with advanced HCC or secondary liver tumors.

There were no dose-limiting toxicities reported; grade 3 adverse effects (AEs) observed in the trial included diarrhea, decreased appetite, fatigue, alanine aminotransferase increase, and aspartate aminotransferase increase.2 Overall, investigators reported a favorable safety profile and identified a recommend phase 2 dose (RP2D) of 200 mg of ezurpimtrostat twice a day.

The first-in-class, first-in-human agent ezurpimtrostat functions by inhibiting palmitoyl protein thioesterase-1. The agent has exhibited high liver tropism and potent anti-tumor activity in HCC in vivo models as monotherapy and in combination with immune checkpoint inhibitors.

Investigators of the multi-center, open-label phase 1/2a trial evaluated ezurpimtrostat among patients with advanced primary and secondary liver cancer. In the dose escalation portion of the trial, patients received 50 mg to 400 mg of ezurpimtrostat once every 3 weeks or 200 to 300 mg twice daily.

The primary end points of the trial were identifying the RPD2 and optimal dosing schedule for ezurpimtrostat. Secondary end points included safety and tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor activity.

Patients 18 years and older with histologically confirmed and documented locally advanced or metastatic HCC that was ineligible for curative therapy and a liver tumor burden of less than 50% were eligible for enrollment. Additional inclusion criteria included having measurable disease per RECIST v1.1 criteria; an ECOG performance status of 0 or1; a life expectancy of at least 12 weeks; adequate hematologic, renal, and hepatic function; and an absence of other clinically relevant abnormalities for screening laboratory test results.

Patients who were pregnant, had any known history of encephalopathy, or clinically significant ascites or paracentesis were not eligible for enrollment on the trial. Patients were also unsuitable for enrollment if they had symptomatic brain metastases, a major surgical procedure within 4 weeks prior to beginning study treatment, severe or uncontrolled renal condition, or untreated chronic hepatitis B.

Investigators are also evaluating ezurpimtrostat in combination with atezolizumab (Tecentriq) and bevacizumab (Avastin) as part of the phase 2b ABE-Liver trial (NCT05448677) and aim to enroll up to 196 patients with HCC.

“We have recently launched our phase 2b clinical trial using ezurpimtrostat in conjunction with the standard atezolizumab/bevacizumab treatment. We are looking forward to sharing the intermediate results in 2024,” Philippe Halfon, MD, PhD, chief executive officer at Genoscience, concluded.


  1. Genoscience Pharma receives FDA orphan drug designation for ezurpimtrostat to treat hepatocellular carcinoma (HCC). News release. Genoscience Pharma. February 1, 2023. Accessed February 10, 2023. bit.ly/40DmxpQ
  2. Harding JJ, Awada A, Roth G, et al. First-in-human effects of PPT1 inhibition using the oral treatment with GNS561/ezurpimtrostat in patients with primary and secondary liver cancers. Liver Cancer. 2022;11(3):268-277. doi:10.1159/000522418
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